(−)-6a,10a-Trans-Δ9-tetrahydrocannabinol (“(−)-Δ9-THC”) is mainly responsible for the antiemetic effects associated with cannabis (S. E. Sallen et al., N. Engl. J. Med. 302:135 (1980); A. E. Chang et al., Cancer 47:1746 (1981); and D. S. Poster et al., J. Am. Med. Asso. 245:2047 (1981)). Both trans-(−)-Δ9-THC and trans-(+)-Δ9-THC, the trans-(−)- and (+)-enantiomers, respectively, of (±)-Δ9-THC, are reported to be useful for treating pain, with trans-(−)-Δ9-THC reported to be more potent than trans-(+)-Δ9-THC (see, e.g., G. Jones et al., Biochem. Pharmacol. 23:439 (1974); S. H. Roth, Can. J. Physiol. Pharmacol. 56:968 (1978); B. R. Martin et al., Life Sciences 29:565 (1981); M. Reichman et al., Mol. Pharmacol. 34:823 (1988); and M. Reichman et al., Mol. Pharmacol. 40:547 (1991)). trans-(−)-Δ9-THC is reported to be useful an antiemetic to relieve nausea and vomiting in patients receiving cancer chemotherapy and to stimulate weight gain in patients suffering from symptomatic HIV infection (see U.S. Pat. No. 6,703,418 B2 to Plasse). An encapsulated formulation of synthetic trans-(−)-Δ9-THC (“dronabinol”) in sesame oil is currently sold as Marinol® by Unimed Pharmaceuticals, Inc., in 2.5, 5, and 10 mg dosage strengths.
Trans-(−)-Δ9-THC can be extracted from hashish (see, Y. Gaoni et al., J. Am. Chem. Soc. 93:217 (1971); and U.S. Pat. No. 6,365,416 B1 to Elsohly et al.). The concentration of trans-(−)-Δ9-THC in hashish, however, ranges from only about 1-5% depending on the source, and, even after extraction, trans-(−)-Δ9-THC must be separated from other impurities such as cannabinoid isomers.
R. F. Turk et al., J. Pharm. Pharmac.23:190-195 (1971) describes a method for isolating trans-(−)-Δ9-THC from marihuana, but the product contained an undetermined amount of carboxylic precursors of THC.
The following paragraphs relate to known methods that purport making trans-(−)-Δ9-THC or (±)-Δ9-THC:
U.S. Pat. No. 3,560,528 to Petrizilka describes the reaction of (+)-p-mentha-2,8-dien-1-ol with olivetol in the presence of p-toluenesulfonic acid monohydrate (“PTSA.H2O”) or trifluoroacetic acid in refluxing benzene to provide (−)-Δ8-THC, which can be converted to trans-(−)-Δ9-THC by addition of HCl followed by dehydrochlorination (see Y. Mechoulam et al., J. Am. Chem. Soc. 89:4553 (1967); and R. Mechoulam et al., J. Am. Chem. Soc. 94:6159 (1972)).
U.S. Pat. No. 4,025,516 to Razdan et al. describes the reaction of a mixture of cis/trans-(+)-p-mentha-2,8-dien-1-ol with olivetol in an inert organic solvent in the presence of an excess of a non-alkaline dehydrating agent and an acid catalyst to form trans-(−)-Δ9-THC; this patent also describes the reaction of (−)-cannabidiol (“(−)-CBD”) or (−)-abnormal-CBD (“(−)-abn-CBD”) with a Lewis acid such as boron trifluoride diethylether (“BF3.Et2O”) in an inert solvent under anhydrous conditions to form trans-(−)-Δ9-THC.
R. K. Razdan et al., J. Am. Chem. Soc. 96:5860 (1974) describes the reaction of a mixture of cis/trans-(+)-p-mentha-2,8-dien-1-ol with olivetol in the presence of 1% BF3.Et2O, methylene chloride and anhydrous magnesium sulfate to form trans-(−)-Δ9-THC.
U.S. Pat. No. 4,381,399 to Olsen et al. describes a method for separating trans-(−)-Δ9-THC from a crude synthetic mixture, the method comprising esterifying the crude mixture, isolating the resultant trans-(−)-Δ9-THC ester, hydrolyzing the ester, and distilling trans-(−)-Δ9-THC at reduced pressure.
K. E. Fahrenholtz et al., J. Am. Chem. Soc. 89:5934-5941 (1967) describes the hydrolysis of (±)-1-m-nitrobenzenesulfoanate-6a,10a-trans-Δ9-tetrahydrocannabinol with NaOH in aqueous methanol to provide (±)-Δ9-THC, which was subsequently crystallized from hexane.
E. G. Taylor et al., J. Am. Chem. Soc. 88:367 (1966) describes the reaction of citral with olivetol in acidified ethanol to form (±)-Δ9-THC in about 35% yield.
S. L. Levin et al., J. Chromatogr. A 654:53-64 (1993) describe a method for resolving trans-(−)-Δ9-THC and trans-(+)-Δ9-THC from a composition comprising equimolar amounts of the trans-(−)- and (+)-enantiomer.
Despite these described methods, there remains a need for improved methods for making trans-(−)-Δ9-THC in pure or substantially pure form.
Citation of any reference in Section 2 of this application is not an admission that the reference is prior art to the application.